Production method of 5-phthalancarbonitrile compound, intermediate therefor and production method of the intermediate

ABSTRACT

The present invention provides a production method of a 5-phthalancarbonitrile compound, which comprises the use of a novel compound of the formula [I] 
                 
 
     wherein X is chlorine atom, bromine atom or iodine atom, as a key intermediate. The method of the present invention imposes small environmental burden (without use of a reagent imposing great burden on the environment, such as heavy metal, metal cyanide, thionyl chloride and the like) and is safe. The inventive method is based on a completely new strategy which is different from conventional production methods of 5-phthalancarbonitrile compound.

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a production method of a5-phthalancarbonitrile compound useful as an intermediate forcitalopram, which is an antidepressant, an intermediate for the5-phthalancarbonitrile compound and a production method of theintermediate for the 5-phthalancarbonitrile compound. More particularly,the present invention relates to a production method of a5-phthalancarbonitrile compound via a novel compound of the formula [I]to be mentioned later, based on a completely new viewpoint.

BACKGROUND OF THE INVENTION

[0002] The 5-phthalancarbonitrile compound of the formula [VI]

[0003] (hereinafter to be also referred to as compound [VI]) is acompound useful as a synthetic intermediate for citalopram of theformula [VII]

[0004] which is an antidepressant. The production method of the5-phthalancarbonitrile compound is known to be as shown in the followingscheme (WO98/19511).

[0005] wherein R is cyano, alkyloxycarbonyl having 2 to 6 carbon atomsor alkylaminocarbonyl having 2 to 6 carbon atoms, and Hal is a halogenatom.

[0006] According to this method, when R is other than cyano, cyanationis necessary after reduction and ring closure reaction. For example,when R is alkyloxycarbonyl, cyanation is carried out by the three stepsof hydrolysis, amidation and reaction with chlorosulfonyl isocyanate,and when R is alkylaminocarbonyl, cyanation is carried out by a reactionwith thionyl chloride or phosphorus pentachloride. In these methods,reagents undesirable to the environment, such as chlorosulfonylisocyanate, thionyl chloride and phosphorus pentachloride, are used, andwhen R is alkyloxycarbonyl, cyanation is carried out by 3 steps, whichis not necessarily simple or easy.

[0007] When R is cyano, the production method of the starting material,5-cyanophthalide, needs to be improved. To be specific, 5-cyanophthalideis known to be obtained by the reaction of a diazonium salt derived from5-aminophthalide with potassium cyanide in the presence of coppersulfide (Bull. Soc. Sci. Bretagne, 26, 1951, 35). This method is notdesirable in that a toxin and a heavy metal salt are involved, such aspotassium cyanide and copper sulfide. In addition, synthesis of5-aminophthalide requires a dangerous reaction of nitration ofphthalimide (Organic Synthesis II, 459), and further, reduction to aminoby tin chloride and semi-reduction of phthalimide by zinc (J. Chem.Soc., 1931, 867), generating a waste heavy metal that is industriallyundesirable.

[0008] It is therefore an object of the present invention to provide aproduction method of a 5-phthalancarbonitrile compound, which placesonly a small burden on the environmental and which is safe.

SUMMARY OF THE INVENTION

[0009] Such object can be achieved by the present invention detailed inthe following.

[0010] In accordance with the present invention, there are provided amethod of producing a 5-phthalancarbonitrile compound (compound of theaforementioned formula [VI]) useful as an intermediate for citalopram,which is safe and imposes less environmental burden, the methodcomprising using a compound of the formula [A]

[0011] wherein R² is alkanoyl having 2 to 5 carbon atoms (hereinafter tobe also referred to as compound [A]) as a starting material, and a novelcompound of the formula [I]

[0012] wherein X is chlorine atom, bromine atom or iodine atom(hereinafter to be also referred to as compound [I]) as a keyintermediate, without using thionyl chloride and the like; novelcompounds of the following formulas [II], [III], [IV] and [V], that canbe used for the production method of the 5-phthalancarbonitrile compoundof the present invention:

[0013] wherein R¹ is alkanoyl having 2 to 5 carbon atoms, alkyl having 1to 5 carbon atoms, tetrahydropyran-2-yl, alkoxymethyl wherein thealkoxyl moiety has 1 to 5 carbon atoms, 1-alkoxyethyl wherein thealkoxyl moiety has 1 or 3 to 10 carbon atoms, or trialkylsilyl whereineach alkyl moiety has 1 to 5 carbon atoms, and X is chlorine atom,bromine atom or iodine atom (hereinafter to be also referred to ascompound [II], compound [III], compound [IV] and compound [V],respectively); and the production methods thereof. Every conventionalproduction method of citalopram goes through a 5-substituted phthalidecompound (e.g., 5-formylphthalide), but the method of the presentinvention goes through the compound [I], employing a completely newsynthetic strategy.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The symbols used in the present specification are defined in thefollowing.

[0015] With regard to alkyl, alkoxy and the like used in the presentinvention, they are linear unless a prefix (e.g., iso, neo etc.) or asymbol (e.g., sec-, tert- etc.) is attached. For example, a simple“propyl” means linear propyl.

[0016] The alkanoyl having 2 to 5 carbon atoms at R¹, R², R^(1′), andR^(1a) is linear or branched chain alkanoyl preferably having 2 to 5carbon atoms, such as acetyl, butanoyl, propanoyl, isopropanoyl,pentanoyl, pivaloyl and the like, with preference given to acetyl,propanoyl and pivaloyl.

[0017] The alkyl having 1 to 5 carbon atoms at R¹, R^(1′)and R^(1b) islinear or branched chain alkyl preferably having 1 to 4 carbon atoms,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl and the like, with preference given tomethyl and tert-butyl.

[0018] The alkoxymethyl at R¹, R^(1′) and R^(1b), wherein the alkoxylmoiety has 1 to 5 carbon atoms, is alkoxymethyl having linear orbranched chain alkoxy preferably having 1 or 2 carbon atoms, such asmethoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl,butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl,pentoxymethyl, isopentoxymethyl and the like, with preference given tomethoxymethyl and ethoxymethyl.

[0019] The 1-alkoxyethyl at R¹, wherein the alkoxyl moiety has 1 or 3 to10 carbon atoms, is linear, branched chain or cyclic 1-alkoxyethylwherein the alkoxyl moiety preferably has 1 or 3 to 6 carbon atoms, suchas 1-methoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-butoxyethyl,1-isobutoxyethyl, 1-sec-butoxyethyl, 1-tert-butoxyethyl, 1-pentoxyethyl,1-isopentoxyethyl, 1-hexyloxyethyl, 1-cyclohexyloxyethyl,1-heptyloxyethyl, 1-octyloxyethyl, 1-nonyloxyethyl, 1-decyloxyethyl andthe like, with preference given to 1-propoxyethyl, 1-butoxyethyl and1-cyclohexyloxyethyl.

[0020] The 1-alkoxyethyl at R^(1′) and R^(1b), wherein the alkoxylmoiety has 1 to 10 carbon atoms, is linear, branched chain or cyclic1-alkoxyethyl wherein the alkoxyl moiety preferably has 1 to 6 carbonatoms, such as 1-methoxyethyl, 1-ethoxyethyl, 1-propoxyethyl,1-isopropoxyethyl, 1-butoxyethyl, 1-isobutoxyethyl, 1-sec-butoxyethyl,1-tert-butoxyethyl, 1-pentoxyethyl, 1-isopentoxyethyl, 1-hexyloxyethyl,1-cyclohexyloxyethyl, 1-heptyloxyethyl, 1-octyloxyethyl,1-nonyloxyethyl, 1-decyloxyethyl and the like, with preference given to1-ethoxyethyl, 1-propoxyethyl, 1-butoxyethyl and 1-cyclohexyloxyethyl.

[0021] The alkyl of the trialkylsilyl at R¹, R^(1′) and R^(1b), whereineach alkyl moiety has 1 to 5 carbon atoms, is independently linear orbranched chain alkyl preferably having 1 to 4 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl and the like, with preference given tomethyl and tert-butyl. The trialkylsilyl may be, for example,trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl,tributylsilyl, triisobutylsilyl, trisecbutylsilyl, tripentylsilyl,triisopentylsilyl, tertbutyldimethylsilyl and the like, with preferencegiven to trimethylsilyl, tributylsilyl and tert-butyldimethylsilyl.

[0022] The present invention is explained in detail in the following.

[0023] Production method of compound [I]

[0024] The novel compound [I] can be efficiently obtained by subjectingcompound [A] to one of chlorination, bromination and iodination, andthen to the elimination of the alkanoyl group. For example,chlorination, bromination or iodination, preferably bromination, isperformed by reacting compound [A] with a halogenating agent in areaction solvent to give a compound of the formula [II-a]

[0025] wherein X is chlorine atom, bromine atom or iodine atom andR^(1a) is alkanoyl having 2 to 5 carbon atoms (hereinafter to be alsoreferred to as compound [II-a]). This reaction is preferably carried outin the presence of a base. As used herein, X is preferably bromine atomin consideration of conversion of the compound of the formula [II-b] toa lithium compound or a Grignard reagent in the later step and R^(1a) isparticularly preferably acetyl in view of the easiness of synthesis anddeprotection. The alkanoyl group is eliminated by adding the obtainedcompound [II-a] or a solution of compound [II-a] in an organic solvent,to an aqueous solution of an acid or base, preferably an acidic aqueoussolution, to allow hydrolysis.

[0026] The starting compound [A] is preferably m-xylylene glycoldiacetate, m-xylylene glycol dipropionate or m-xylylene glycoldipivalate.

[0027] The reaction solvent to be used for chlorination, bromination andiodination is, for example, glacial acetic acid, aqueous acetic acidsolution (concentration:60-100 wt %, preferably 80-100 wt %), water,monochlorobenzene, o-dichlorobenzene, ethyl acetate, tert-butyl methylether, and methanol, ethanol, isopropyl alcohol, acetone etc., that maycontain water, with preference given to glacial acetic acid, aqueousacetic acid solution, methanol, o-dichlorobenzene and ethyl acetate. Thereaction solvent is used in an amount of generally 1 L-20 L, preferably3 L-10 L, per 1 kg of compound [A].

[0028] The base to be used for chlorination, bromination and iodinationis sodium acetate, potassium acetate, sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, sodium methoxide,sodium ethoxide and the like, preferably sodium acetate, potassiumacetate, sodium hydroxide, potassium hydroxide, sodium carbonate andpotassium carbonate. The base is used in an amount of generally 0.1equivalent-10 equivalents, preferably 0.8 equivalent-6 equivalents, perthe amount of compound [A].

[0029] The halogenating agent to be used for chlorination, brominationand iodination is bromine, chlorine, N-bromosuccinimide,N-chlorosuccinimide, sulfuryl chloride and the like, preferably bromineand N-bromosuccinimide. The halogenating agent is used in an amount ofgenerally 0.8 mol-8 mol, preferably 2 mol-6 mol, per 1 mol of compound[A].

[0030] For chlorination and bromination, a catalyst may be added toaccelerate the reaction. The catalyst may be a single metal such asiron, copper, zinc, aluminum and the like; or a metal halide such asiron(I) chloride, iron(II) chloride, aluminum chloride, aluminumbromide, copper(I) chloride, copper(II) chloride, magnesium chloride,magnesium bromide, magnesium iodide, titanium tetrachloride, zincchloride, zinc bromide, zinc iodide and the like, with preference givento iron, iron(I) chloride, iron(II) chloride, magnesium chloride,magnesium bromide, zinc chloride, zinc bromide and zinc iodide. Thecatalyst is used in an amount of generally 0.0001 mol-0.5 mol,preferably 0.001 mol-0.2 mol, per 1 mol of compound [A].

[0031] The reaction temperature of chlorination, bromination andiodination is generally from −30° C. to 80° C., preferably from 0° C. to50° C., and the reaction time is generally 30 min-24 hr, preferably 2hr-18 hr.

[0032] When compound [A] is subjected to chlorination, bromination oriodination, a 2,6-disubstituted compound may be produced as a halide,besides the compound [II-a] which is a 2,4-disubstituted compound. Suchhalide is isolated by, for example, pouring the reaction mixture to areducing aqueous solution (e.g., aqueous sodium sulfite solution andaqueous sodium thiosulfate solution etc.) under ice-cooling, or pouringa reducing aqueous solution into the reaction mixture, adding an organicsolvent, extraction and evaporation of the solvent. The compound [II-a]can be isolated from the mixture of halide by silica gel columnchromatography, recrystallization and the like. The compound [II-a] mayor may not be isolated from the mixture of halide. When the compoundsare subjected to the next step without isolation, the corresponding2,6-disubstituted compound, such as 2,6-disubstituted compound ofcompound [I] and 2,6-disubstituted compound of the compound of theformula [II-b] to be mentioned later, is obtained in each step togetherwith the reaction product.

[0033] The amount of water to be used for elimination of the alkanoylgroup is generally 0.5 L-20 L, preferably 3 L-10 L, per 1 kg of halide(mixture when halide is a mixture). A solvent inert to the reaction maybe concurrently used, such as alcohol solvent (e.g., methanol, ethanoletc.), tetrahydrofuran (THF), dioxane and the like, which may be used todissolve halide. When the solvent is used for dissolution of halide, itis used in an amount of generally 0.5 L-20 L, preferably 2 L-10 L, per 1kg of halide (mixture when halide is a mixture).

[0034] The acid to be used for the elimination of the alkanoyl group isnot particularly limited as long as it is typically used for thispurpose. Examples thereof include inorganic acid such as hydrochloricacid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoricacid and the like; organic acid such as formic acid, acetic acid,propionic acid, trifluoroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid and the like; and the like, withpreference given to hydrochloric acid, hydrobromic acid and sulfuricacid. The amount of the acid to be used is generally 0.001 kg-10 kg,preferably 0.01 kg-0.3 kg, per 1 kg of halide (mixture when halide is amixture).

[0035] The base to be used for the elimination of the alkanoyl group isnot particularly limited as long as it is typically used for thispurpose. Examples thereof include inorganic base such as hydroxide,carbonate or hydrogencarbonate of alkali metal (e.g., lithium, sodium,potassium etc.) or alkaline earth metal (e.g., calcium, magnesium etc.)and alkoxide (e.g., methoxide, ethoxide etc.) of alkali metal, andorganic base such as trialkylamine (e.g., trimethylamine, triethylamineetc.), with preference given to sodium hydroxide, potassium hydroxide,potassium carbonate and sodium methoxide. The amount of the base to beused is generally 0.8 equivalent-10 equivalents, preferably 1equivalent-5 equivalents, per halide (mixture when halide is a mixture).

[0036] The reaction temperature of the elimination of the alkanoyl groupis generally from −20° C. to 100° C., preferably from 10° C. to 80° C.,and the reaction time is generally 10 min-24 hr, preferably 30 min-8 hr.

[0037] The compound [I] is isolated by a conventional method, such ascrystallization after neutralization of the reaction mixture.

[0038] Production method of compound [II′]

[0039] A compound of the formula [II′]

[0040] wherein R^(1′) is alkanoyl having 2 to 5 carbon atoms, alkylhaving 1 to 5 carbon atoms, tetrahydropyran-2-yl, alkoxymethyl whereinthe alkoxyl moiety has 1 to 5 carbon atoms, 1-alkoxyethyl wherein thealkoxyl moiety has 1 to 10 carbon atoms, or trialkylsilyl wherein eachalkyl moiety has 1 to 5 carbon atoms, and X is chlorine atom, bromineatom or iodine atom (hereinafter to be referred to as compound [II′]),consists of compound [II-a] and a compound of the formula [II-b]

[0041] wherein R^(1b) is alkyl having 1 to 5 carbon atoms,tetrahydropyran-2-yl, alkoxymethyl wherein the alkoxyl moiety has 1 to 5carbon atoms, 1-alkoxyethyl wherein the alkoxyl moiety has 1 to 10carbon atoms or trialkylsilyl wherein each alkyl moiety has 1 to 5carbon atoms, and X is chlorine atom, bromine atom or iodine atom(hereinafter to be referred to as compound [II-b]). A compound whereinonly 1-ethoxyethyl is excluded from the substituents at R^(1′) ofcompound [II′] corresponds to novel compound [II]. The compound [II′]can be obtained by

[0042] (a) converting the hydroxyl group of compound [I] to alkoxyhaving 1 to 5 carbon atoms, tetrahydropyran-2-yloxy, alkoxymethoxywherein the alkoxyl moiety has 1 to 5 carbon atoms, 1-alkoxyethoxywherein the alkoxyl moiety has 1 to 10 carbon atoms or trialkylsilyloxywherein each alkyl moiety has 1 to 5 carbon atoms, or by

[0043] (b) subjecting compound [A] to chlorination, bromination oriodination.

[0044] The step (a) is explained in the following. By (a), compound[II-b] can be obtained. The hydroxyl group can be converted to eachgroup by any method generally used for converting hydroxyl group to suchgroup. It is converted to 1-alkoxyethoxy by, for example, reactingcompound [I] with alkyl vinyl ether of the formula :R³CH═CH₂ wherein R³is alkoxy having 1 to 10 carbon atoms, in a reaction solvent in thepresence of a catalyst.

[0045] The starting compound [I] is preferably2,4-bis(hydroxymethyl)bromobenzene in consideration of conversion to alithium compound or a Grignard reagent of the compound [III] in thelater step.

[0046] The alkoxy having 1 to 10 carbon atoms at R³ of the above formulacorresponds to alkoxy of 1-alkoxyethyl at the substituent R^(1′) incompound [II′], wherein the alkoxyl moiety has 1 to 10 carbon atoms. Thealkyl vinyl ether to be used for the reaction is, for example, methylvinyl ether, ethyl vinyl ether, propyl vinyl ether, isopropyl vinylether, butyl vinyl ether, pentyl vinyl ether, cyclohexyl vinyl ether,hexyl vinyl ether, heptyl vinyl ether, octyl vinyl ether, nonyl vinylether, decyl vinyl ether and the like, preferably ethyl vinyl ether,propyl vinyl ether, butyl vinyl ether or cyclohexyl vinyl ether. Theamount of the alkyl vinyl ether to be used is generally 2 mol-4 mol,preferably 2 mol-3 mol, per 1 mol of compound [I].

[0047] As the catalyst, for example, p-toluenesulfonic acid,methanesulfonic acid, sulfuric acid, hydrochloric acid, trifluoroaceticacid, trifluoromethanesulfonic acid, and an acidic ion exchange resinsuch as Amberlyst 15E, Amberlite IR-118 etc. are used, with preferencegiven to p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid andhydrochloric acid. These catalysts can be also used in the form of ahydrate. The amount of the catalyst to be used is generally 0.0001mol-0.2 mol, preferably 0.0005 mol-0.01 mol, per 1 mol of compound [I].

[0048] The reaction solvent may be, for example, toluene, xylene,monochlorobenzene, methylene chloride, acetone, methyl ethyl ketone,methyl isobutyl ketone, ethyl acetate and the like, with preferencegiven to toluene, xylene, monochlorobenzene and methylene chloride. Theamount of the reaction solvent to be used is generally 1 L-20 L,preferably 2 L-12 L, per 1 kg of compound [I].

[0049] The reaction temperature is generally from −20° C. to 120° C.,preferably from 0° C. to 60° C., and the reaction time is generally 10min-10 hr, preferably 30 min-6 hr. The objective compound can beisolated by a conventional method (e.g., extraction, etc.).

[0050] Conversion to a group other than 1-alkoxyethoxy is performedaccording to a conventional method. For the conversion to alkoxy, forexample, a reagent such as R⁴OH wherein R⁴ is alkyl having 1 to 5 carbonatoms, R⁴Br wherein R⁴ is as defined above, R⁴I wherein R⁴ is as definedabove, and (R⁴)₂SO₄ wherein R⁴ is as defined above is used; for theconversion to tetrahydropyran-2-yloxy, for example, a reagent such as3,4-dihydro-2[H]-pyran is used; for the conversion to alkoxymethoxy, forexample, a reagent, such as R⁵OCH₂OH wherein R⁵ is alkyl having 1 to 5carbon atoms, R⁵OCH₂OR⁵ wherein R⁵ is as defined above, R⁵OCH₂Cl whereinR⁵ is as defined above and R⁵OCH₂Br wherein R⁵ is as defined above isused; and for the conversion to trialkylsilyloxy, for example, areagent, such as (R⁶)₃SiCl wherein R⁶ is alkyl having 1 to 5 carbonatoms, is used. The definition of the above R⁴-R⁶ is the same as in thecorresponding R^(1′).

[0051] Then, compound [II-a] can be obtained by (b). The chlorination,bromination and iodination of compound [A] in (b) are carried out in thesame manner as in those for the production of compound [I]. Brominationis preferably carried out in consideration of conversion of the compound[II-b] to a lithium compound or a Grignard reagent in the later step.

[0052] The compound [II-b] can be also obtained by a method other thanthe above-mentioned (a). For example, a compound [II-b] wherein R^(1b)is alkyl having 1 to 5 carbon atoms can be obtained by

[0053] Step 1: m-xylylene dichloride is reacted with an alkali metalalkoxide of the formula R′OM, wherein R′ is alkyl having 1 to 5 carbonatoms and M is alkali metal, in a reaction solvent to give1,3-bis(alkoxymethyl)benzene, and

[0054] Step 2: the resulting compound is subjected to chlorination,bromination or iodination.

[0055] Step 1 is explained in detail in the following. In this step,alkali metal alkoxide is added to m-xylylene dichloride in a reactionsolvent to give 1,3-bis(alkoxymethyl)benzene.

[0056] The reaction solvent in Step 1 is exemplified by alcohol solvent(e.g., methanol, ethanol, isopropyl alcohol, tert-butyl alcohol etc.),tetrahydrofuran (THF), tert-butyl methyl ether, toluene,monochlorobenzene, N,N-dimethylformamide, dimethyl sulfoxide and thelike. The amount of the solvent to be used is generally 1 L-30 L,preferably 2 L-15 L, per 1 kg of m-xylylene dichloride.

[0057] The alkyl moiety of the alkali metal alkoxide in Step 1 is thesame as those exemplified for the alkyl at R^(1b) and examples of alkalimetal include sodium, potassium and the like. Preferable examples ofalkali metal alkoxide include sodium methoxide and potassiumtert-butoxide. The amount of the alkali metal alkoxide to be used isgenerally 1.8 mol-4 mol, preferably 2 mol-3.2 mol, per 1 mol ofm-xylylene dichloride.

[0058] The reaction temperature in Step 1 is generally from −30° C. to100° C., preferably 20° C.-70° C., and the reaction time is generally0.5 hr-10 hr, preferably 1 hr-6 hr.

[0059] The isolation of 1,3-bis(alkoxymethyl)benzene can be carried outby a conventional method, such as extraction and drying afterevaporation of the solvent.

[0060] Step 2 can be carried out in the same manner as in chlorination,bromination, iodination in the production method of compound [I] andunder the same reaction conditions. The reaction solvent, base,halogenating agent and catalyst to be used for the chlorination,bromination and iodination are the same as those exemplified for theproduction method of compound [I], wherein they are used in the sameamounts as in the production method of compound [I]. The reactionproduct can be isolated in the same manner as in the production methodof compound [I].

[0061] Production method of compound [III]

[0062] A novel compound [III] can be obtained by

[0063] (a) converting compound [II-b] to Grignard reagent or lithiumcompound,

[0064] (b) coupling the resulting compound with p-fluorobenzaldehyde and

[0065] (c) subjecting the obtained coupling compound to deprotection ofR^(1b) and cyclization.

[0066] The compound [II-b] is compound [I], wherein hydroxyl group hasbeen protected, which is, after conversion to a lithium compound or aGrignard reagent, reacted with p-fluorobenzaldehyde. Therefore, X in thecompound [II-b] is free of any particular limitation as long as compound[II-b] can be converted to a lithium compound or a Grignard reagent.Preferred is bromine atom in view of the quick conversion and thestability of the lithium compound or Grignard reagent after conversion.For easy deprotection, tetrahydropyran-2-yl, alkoxymethyl, where alkoxyhas 1 to 5 carbon atoms, 1-alkoxyethyl, where alkoxy has 1 to 10 carbonatoms, and trialkylsilyl, where each alkyl has 1 to 5 carbon atoms, arepreferable as R^(1b), with more preference given totetrahydropyran-2-yl, methoxymethyl and 1-alkoxyethyl, where alkoxy has1 to 10 carbon atoms, particularly preferably 1-ethoxyethyl,1-propoxyethyl, 1-butoxyethyl and 1-cyclohexyloxyethyl. From theeasiness of synthesis, methyl and tert-butyl are particularlypreferable.

[0067] As compound [II-b], preferred are 2,4-bis(1′-ethoxyethoxymethyl)bromobenzene, 2,4-bis(1′-butoxyethoxymethyl)-bromobenzeneand 2,4-bis(1′-cyclohexyloxyethoxymethyl)bromobenzene.

[0068] The above-mentioned (a) to (c) are explained in this order in thefollowing.

[0069] (a): The compound [II-b] can be converted to a Grignard reagentor a lithium compound by a method conventionally known, which is usedfor obtaining a Grignard reagent or a lithium compound from halide. Forexample, compound [II-b] is reacted with metal magnesium in an organicsolvent, or a solution of an organic lithium compound in an organicsolvent, and may be added dropwise to compound [II-b]. The metalmagnesium or organic lithium compound is added in an amount generallynecessary for converting a halide to a Grignard reagent or a lithiumcompound. For example, metal magnesium is added in an amount ofgenerally 0.9 mol-3 mol, preferably 1 mol-1.5 mol, and the organiclithium compound is added in an amount of generally 0.9 mol-1.5 mol,preferably 1 mol-1.3 mol, both per 1 mol of compound [II-b]. Examples ofthe organic lithium compound include n-butyl lithium, phenyl lithium,methyl lithium, sec-butyl lithium and tert-butyl lithium, preferablyn-butyl lithium and methyl lithium. For the easiness of the operationand the yield of the reaction, compound [II-b] is preferably convertedto a lithium compound.

[0070] The organic solvent is exemplified by ether solvents (e.g.,tetrahydrofuran (THF), tert-butyl methyl ether, dimethoxyethane, dibutylether, ethyl ether etc.), hexane, heptane, toluene, xylene and the like,with preference given to hexane, THF, tert-butyl methyl ether anddimethoxyethane. The amount of the organic solvent to be used isgenerally 1 L-30 L, preferably 5 L-20 L, per 1 kg of compound [II-b].

[0071] The reaction temperature in (a) is generally from −78° C. to 30°C., preferably from −50° C. to −10° C., and the reaction time isgenerally 10 min-6 hr, preferably 10 min-2 hr. The reaction mixtureobtained in (a) can be isolated or purified by a conventional method.Alternatively, it may be subjected to the next reaction as it isobtained.

[0072] (b): p-Fluorobenzaldehyde is added dropwise to the reactionmixture of (a) for coupling reaction. The amount of p-fluorobenzaldehydeto be used is generally 0.8 mol-3 mol, preferably 1 mol-1.5 mol, per 1mol of compound [II-b]. p-Fluorobenzaldehyde can be added as a solutionin an organic solvent, wherein the organic solvent is free of anyparticular limitation and exemplified by tetrahydrofuran, tert-butylmethyl ether, dimethoxyethane, hexane, heptane and the like.

[0073] The reaction temperature in (b) is generally from −78° C. to 60°C., preferably from −50° C. to 30° C., and the reaction time isgenerally 10 min-6 hr, preferably 10 min-2 hr.

[0074] After the completion of the reaction, a basic aqueous solution(e.g., aqueous ammonium chloride solution), an acidic aqueous solution(e.g., aqueous acetic acid solution) and the like are added to hydrolyzethe reaction product. The coupling compound after hydrolysis can beisolated by, for example, partitioning and evaporation of the solvent.

[0075] (c): The isolated coupling compound is reacted with an acidcatalyst in a reaction solvent for the deprotection of R^(1b) andcyclization. The method of addition is not particularly limited. Forexample, an acid catalyst may be added to the reaction mixture of thecoupling compound. The reaction is preferably carried out under pressureof generally 2 kPa-110 kPa, preferably 5 kPa-80 kPa, while removingdeprotected aldehydes having a low boiling point, thereby suppressingthe occurrence of by-product.

[0076] The reaction solvent may be water alone, because the reactionproceeds sufficiently. A suitable organic solvent may be further added.The organic solvent to be added may be miscible with water ornon-miscible with water. Examples thereof include methanol, ethanol,isopropyl alcohol, acetone, tetrahydrofuran, toluene and xylene. Theamount of the reaction solvent to be used is generally 0.5 L-20 L,preferably 1 L-10 L, per 1 kg of compound [II-b].

[0077] The acid catalyst may be a typical mineral acid, acidic ionexchange resin and Lewis acid, preferably phosphoric acid, sulfuricacid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid,trifluoroacetic acid and trifluoromethanesulfonic acid. The amount ofthe acid catalyst to be used is generally 0.1 mmol-30 mol, preferably0.1 mol-20 mol, per 1 mol of compound [II-b]. The acidic catalyst can bealso used in the form of an aqueous solution.

[0078] The reaction temperature in (c) is generally 30° C.-150° C.,preferably 50° C.-100° C., and the reaction time is generally 10 min-20hr, preferably 1 hr-6 hr.

[0079] The objective compound (compound [III]) can be isolated by aconventional method (e.g., filtration, recrystallization etc.).

[0080] The compound [III] can be obtained via a Grignard reagent orlithium compound of compound [II-b] and then through a coupling compoundof the formula

[0081] wherein R¹ is as defined above.

[0082] Production method of compound [IV]

[0083] The novel compound [IV] can be obtained by oxidation of compound[III]. The compound [III] has, as an easily oxidizable moiety, the1-position and 3-position carbons, besides hydroxymethyl at the5-position of the 1,3-dihydroisobenzofuran ring. Therefore, oxidation ofcompound [III] may accompany oxidation of the 1-position and 3-positioncarbons as a side reaction. However, when compound [III] is oxidizedwith hypochlorite in the presence of an N-oxy radical catalyst,hydroxymethyl is selectively oxidized to give compound [IV] at a highyield. To be specific, hypochlorite is added, preferably added dropwiseas an aqueous solution, to a solution of compound [III] in an organicsolvent in the presence of a base, a catalyst and an N-oxy radicalcatalyst, to give compound [IV].

[0084] The hypochlorite to be used for the oxidation may be, forexample, sodium hypochlorite, potassium hypochlorite, calciumhypochlorite and the like, preferably sodium hypochlorite. The amount ofthe hypochlorite to be used is generally 0.8 mol-2 mol, preferably 0.85mol-1.3 mol, per 1 mol of compound [III]. Sodium hypochlorite ispreferably used in the form of an aqueous solution, where theconcentration of the aqueous solution is generally 8 wt %-15 wt %,preferably 11 wt %-14 wt %.

[0085] The N-oxy radical catalyst to be used for the oxidation may be,for example, 4-substituted-2,2,6,6-tetramethyl-1-piperidinoxy. Theamount of the catalyst to be used is generally 0.0001 mol-0.1 mol,preferably 0.0001 mol-0.01 mol, per 1 mol of compound [III]. Examples ofthe 4-position substituent include hydrogen atom, hydroxyl group, alkoxyhaving 1 to 10 carbon atoms, acyloxy having an aliphatic hydrocarbonresidue having 1 to 10 carbon atoms, carbonylamino having an aliphatichydrocarbon residue having 1 to 10 carbon atoms and the like,particularly preferably hydroxyl group from the viewpoint of the yield.

[0086] The alkoxy having 1 to 10 carbon atoms is preferably linear orbranched chain alkoxy having 1 to 5 carbon atoms, such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentoxy, isopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy anddecyloxy, preferably methoxy, ethoxy and isopropoxy.

[0087] The acyloxy having an aliphatic hydrocarbon residue having 1 to10 carbon atoms is linear or branched chain acyloxy having an aliphatichydrocarbon residue preferably having 1 to 6 carbon atoms, such asacetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,isovaleryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy,nonanoyloxy, decanoyloxy, undecanoyloxy, acryloyloxy andmethacryloyloxy, preferably acetyloxy and methacryloyloxy.

[0088] The carbonylamino having an aliphatic hydrocarbon residue having1 to 10 carbon atoms is a linear or branched chain carbonylamino thathas aliphatic hydrocarbon residue preferably having 1 to 6 carbon atoms,such as acetylamino, propionylamino, butyrylamino, isobutyrylamino,valerylamino, isovalerylamino, pivaloylamino, hexanoylamino,heptanoylamino, octanoylamino, nonanoylamino, decanoylamino,undecanoylamino, acryloylamino and methacryloylamino, preferablyacetylamino.

[0089] Examples of 4-substituted-2,2,6,6-tetramethyl-1-piperidinoxypreferably include 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinoxy,4-methacryloyloxy-2,2,6,6-tetramethyl-1-piperidinoxy,4-acetyloxy-2,2,6,6-tetramethyl-1-piperidnoxy and4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy, particularlypreferably 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinoxy from the aspectof yield.

[0090] The base is free of any particular limitation as long as it doesnot interfere with the reaction, and is exemplified by sodiumhydrogencarbonate, sodium carbonate, potassium hydrogencarbonate,potassium carbonate, lithium carbonate and the like, with preferencegiven to sodium hydrogencarbonate and potassium hydrogencarbonate. Theamount of the base to be used is generally 0.01 mol-2 mol, preferably0.1 mol-0.9 mol, per 1 mol of compound [III].

[0091] Examples of the catalyst include phase transfer catalyst such astetrabutylammonium bromide, tetrabutylammonium chloride,tetrabutylammonium iodide, tetrabutylammonium sulfate,benzyltriethylammonium chloride, benzyltrimethylammonium chloride andthe like, and metal halide catalyst such as potassium iodide, potassiumbromide, sodium iodide, sodium bromide and the like, with preferencegiven to tetrabutylammonium bromide, benzyltriethylammonium chloride,potassium iodide and potassium bromide. The amount of the catalyst to beused is generally 0.0001 mol-0.3 mol, preferably 0.01 mol-0.2 mol, per 1mol of compound [III].

[0092] The organic solvent is not particularly limited and may be, forexample, ethyl acetate, butyl acetate, acetone, ethyl methyl ketone,isobutyl methyl ketone, toluene, xylene, tert-butyl methyl ether and thelike, with preference given to ethyl acetate, acetone, ethyl methylketone, isobutyl methyl ketone and toluene. The amount of the solvent tobe used is generally 1 L-20 L, preferably 3 L-10 L, per 1 kg of compound[III].

[0093] The reaction temperature is generally from −30° C. to 100° C.,preferably 0° C.-50° C., and the reaction time is generally 10 min-10hr, preferably 10 min-2 hr.

[0094] The objective compound can be isolated by a conventional methodsuch as extraction and crystallization.

[0095] Production method of 5-phthalancarbonitrile compound

[0096] The compound [VI] (5-phthalancarbonitrile compound) is anintermediate for the production of citalopram. It can be obtained byreacting a novel compound [IV] with hydroxylamine or a mineral acid saltthereof and via a novel compound [V] (compound [V] in the presentinvention includes both syn-compound and anti-compound), namely, throughoximation (condensation) and dehydration reaction. It is preferable to(a) directly subject the compound [V] to dehydration reaction withoutisolation to make the manipulation simpler. For example, compound [IV]and hydroxylamine or a mineral acid salt thereof are added to an organicsolvent and the mixture is heated as it is to give compound [VI].

[0097] For a higher purity of the compound [VI], (b) compound [V] ispreferably isolated and then subjected to dehydration reaction. Thecompound [V] is obtained by reacting compound [IV] with hydroxylamine ora mineral acid salt thereof. By dehydrating compound [V], compound [VI]is obtained. To be specific, compound [IV] and hydroxylamine or amineral acid salt thereof are added to an organic solvent, and themixture is stirred to give compound [V]. The obtained compound [V] isisolated and heated to give compound [VI]. The compound [V] is isolatedby a conventional method.

[0098] Examples of mineral acid salt of hydroxylamine include salts ofhydroxylamine with hydrochloric acid, sulfuric acid, phosphoric acid,nitric acid and the like, with preference given to hydroxylaminehydrochloride and hydroxylamine sulfate.

[0099] The amount of the hydroxylamine or a mineral acid salt thereof tobe used is generally 0.8 equivalent-5 equivalents, preferably 0.9equivalent-2 equivalents, per compound [IV]. The hydroxylamine and amineral acid salt thereof are used as they are or preferably in asolution state (e.g., methanol, ethanol, isopropyl alcohol, water,etc.). Depending on the scale of the reaction, it is particularlypreferably added dropwise as a solution of hydroxylamine or a mineralacid salt thereof in methanol at 20-50° C.

[0100] Particularly when a hydroxylamine mineral acid salt is used, asuitable base is preferably added in an amount of 1 equivalent to 5equivalents per hydroxylamine mineral acid salt. The base is free of anyparticular limitation as long as it exerts less influence on cyano, andexamples thereof include organic base (e.g., triethylamine,tributylamine, dimethylaniline, pyridine, sodium methoxide, sodiumethoxide, potassium t-butoxide, sodium t-butoxide etc.), inorganic base(e.g., sodium carbonate, sodium hydrogencarbonate, sodium hydroxide,potassium carbonate, potassium hydrogencarbonate, potassium hydroxideetc.), with preference given to triethylamine. It is industriallypreferable to add a base before the addition of a hydroxylamine mineralacid salt.

[0101] To carry out the dehydration reaction of compound [V] under mildconditions, a dehydrating agent may be further added. Examples of thedehydrating agent include acid anhydride (e.g., acetic anhydride,phthalic anhydride etc.), methanesulfonyl chloride, p-toluenesulfonylchloride and the like, with preference given to the use of aceticanhydride from the aspects of the environment and yield. The amount ofthe dehydrating agent to be used is preferably 0.8 equivalent-5equivalents, per hydroxylamine or a mineral acid salt thereof in thecase of above (a), and 1 equivalent-10 equivalents, preferably 1equivalent-5 equivalents, per compound [V] in the case of above (b). Inthe above (a), the dehydrating agent may be added simultaneously withhydroxylamine or a mineral acid salt thereof. However, the additionafter the addition of hydroxylamine or a mineral acid salt thereof ispreferable.

[0102] The organic solvent is free of any particular limitation as longas it does not interfere with the reaction, and examples thereof includemethanol, ethanol, isopropyl alcohol, ethyl acetate, acetonitrile,toluene, xylene, chlorobenzene, 1,2-dichlorobenzene,N-methylpyrrolidone, nitroethane, dimethylformamide, dimethylacetamide,dimethyl sulfoxide, dichloromethane, and mixed solvents of the above,with preference given to acetonitrile, toluene, xylene,N-methylpyrrolidone, nitroethane, ethyl acetate, a mixed solvent ofethyl acetate and methanol, a mixed solvent of ethyl acetate andethanol, a mixed solvent of ethyl acetate and isopropyl alcohol, and amixed solvent of toluene and methanol. The amount of the organic solventto be used is generally 0.5 L-50 L, preferably 1 L-20 L, per 1 kg ofcompound [IV] in the case of above (a), and generally 0.5 L-50 L,preferably 1 L-20 L, per 1 kg of compound [IV] in the case of above (b).

[0103] The reaction temperature in the above (a) is generally 50°C.-220° C., preferably 80° C.-150° C., and the reaction time isgenerally 1 hr-20 hr, preferably 2 hr-8 hr.

[0104] In the above (b), oximation (condensation) is conducted generallyat 20-120° C., preferably 40-100° C., generally for 10 min-4 hr,preferably 30 min-2 hr, and dehydration reaction is carried outgenerally at 60-160° C., preferably 120-150° C., more preferably125-150° C., generally for 30 min-8 hr, preferably 90 min-6 hr.

[0105] The objective compound is isolated by a conventional method suchas extraction and crystallization after neutralization of the reactionmixture.

[0106] The starting compound [A] can be produced according to the methoddescribed in, for example, J. Phys. Org. Chem., 3(12), 789-98 (1990).

[0107] According to the method of the present invention, a5-phthalancarbonitrile compound can be produced without using a reagentthat imposes a great burden on the environment, such as heavy metal,metal cyanide and thionyl chloride. Moreover, the reaction proceedsefficiently throughout the entire steps.

[0108] The 5-phthalancarbonitrile compound can be converted tocitalopram according to the method described in WO98/19511, therebyproducing citalopram useful as an antidepressant.

[0109] The present invention is explained in detail by referring toillustrative examples, but the present invention is not limited by theseexamples in any way. In the examples, the unit % relative to the reagentis wt %.

Example 1

[0110] Synthesis of 2,4-bis(acetoxymethyl)bromobenzene

[0111] To a suspension of m-xylylene glycol diacetate (28.4 g) andsodium acetate (55.2 g) dispersed in glacial acetic acid (130 ml) wasadded dropwise bromine (102.5 g) over 30 min at 15-20° C., and themixture was stirred at 20-30° C. for 13 hr. The reaction mixture waspoured into 10% aqueous sodium sulfite solution (700 ml) in an ice bath.The mixture was stirred and extracted twice with ethyl acetate (250 ml).The ethyl acetate layer was washed 3 times with 10% aqueous sodiumhydrogencarbonate solution (300 ml) and the solvent was evaporated togive an about 93:7 mixture (37.6 g, 97.6%) of2,4-bis(acetoxymethyl)bromobenzene and2,6-bis(acetoxymethyl)bromobenzene as a yellow oil.2,4-bis(Acetoxymethyl)bromobenzene was isolated by preparative HPLC andused in the measurement.

[0112] the mixture:

[0113] n_(D) ²⁴ 1.5310;

[0114] IR(neat)ν=2957(w), 1743(s), 1476(m), 1378(m), 1226(s), 1028(s),858(w), 820(w)cm⁻¹

[0115] 2,4-bis(Acetoxymethyl)bromobenzene:

[0116]¹H-NMR(CDCl₃, 400 MHz)δ=2.11(3H,s), 2.15(3H,s), 5.07(2H,s),5.19(2H,s), 7.19(1H,dd,J=8 Hz,J=2 Hz), 7.39(1H,d,J=2 Hz), 7.57(1H,d,J=8Hz) ppm

Example 2

[0117] Synthesis of 2,4-bis(hydroxymethyl)bromobenzene

[0118] An about 93:7 mixture (36.7 g) of2,4-bis(acetoxymethyl)-bromobenzene and2,6-bis(acetoxymethyl)bromobenzene was dissolved in methanol (183 ml)and cooled to 10° C. To this solution was added dropwise 10% aqueoussodium hydroxide solution (133 g). The reaction mixture was stirred atroom temperature for 1 hr, and the solvent (about 200 ml) wasevaporated. The residue was neutralized with dilute hydrochloric acid(about 200 ml). To the neutralized solution was added toluene (150 ml)and the mixture was stirred at 80-85° C. for 1 hr and cooled. Theresulting crystals were collected by filtration and dried under reducedpressure to give an about 93:7 mixture (22.2 g, 83.7%) of2,4-bis(hydroxymethyl)bromobenzene and2,6-bis(hydroxymethyl)-bromobenzene as almost white crystals.2,4-bis(Hydroxymethyl)-bromobenzene was isolated by preparative HPLC andused in the measurement.

[0119] mixture:

[0120] melting point 106-108° C.;

[0121] IR(KBr)ν=3307(br), 1467(s), 1413(s), 1228(s), 1158(s), 1063(s),1002(s), 824(s), 741(s), 641(s) cm⁻¹

[0122]2,4-bis(Hydroxymethyl)bromobenzene:

[0123]¹H-NMR(DMSO-d₆, 400 MHz)δ=4.46(2H,d,J=5 Hz), 4.49(2H,d,J=5 Hz),5.26(1H,t,J=5 Hz), 5.41(1H,t,J=5 Hz), 7.12(1H,dd,J=8 Hz,J=2 Hz),7.48(1H,d,J=8 Hz), 7.50(1H,d,J=2 Hz) ppm

Example 3

[0124] Synthesis of 2,4-bis(1-ethoxyethoxymethyl)bromobenzene

[0125] To a suspension obtained by dispersing an about 93:7 mixture(22.1 g) of 2,4-bis(hydroxymethyl)bromobenzene and2,6-bis(hydroxymethyl)bromobenzene, and p-toluenesulfonic acidmonohydrate (0.1 g) in toluene (220 ml) was added dropwise ethyl vinylether (18.4 g) at 24-32° C., and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was poured into 5% aqueoussodium carbonate solution (100 ml), and the organic layer was washedwith 5% aqueous sodium carbonate solution (100 ml), and dried overpotassium carbonate. The solvent was evaporated to give an about 93:7mixture (35.7 g, 97.1%) of 2,4-bis(1′-ethoxyethoxymethyl)bromobenzeneand 2,6-bis(1′-ethoxyethoxymethyl)bromobenzene as a yellow oil.2,4-bis(1′-Ethoxyethoxymethyl)bromobenzene was isolated by preparativeHPLC and used in the measurement.

[0126] 2,4-bis(1′-Ethoxyethoxymethyl)bromobenzene:

[0127]¹H-NMR(CDCl₃, 400 MHz)δ=1.22(3H,t,J=7 Hz), 1.23(3H,t,J=7 Hz),1.36(3H,d,J=5 Hz), 1.41(3H,d,J=5 Hz), 3.48-3.59(2H,m), 3.63-3.75(2H,m),4.49(1H,d,J=12 Hz), 4.58(1H,d,J=13 Hz), 4.61(1H,d,J=12 Hz),4.69(1H,d,J=13 Hz), 4.81(1H,q,J=5 Hz), 4.88(1H,q,J=5 Hz), 7.14(1H,dd,J=8Hz,J=2 Hz), 7.47(1H,d,J=2 Hz), 7.50(1H,d,J=8 Hz) ppm

Example 4

[0128] Synthesis of 2,4-bis(methoxymethyl)bromobenzene

[0129] To a solution of m-xylylene dichloride (25.0 g) in methanol (125ml) was added a 28% methanol solution (82.6 g) containing sodiummethoxide at room temperature, and the mixture was stirred with heatingat 60° C. for 3 hr. The solvent was evaporated and water (150 ml) wasadded to the residue. The mixture was extracted twice with heptane (80ml) and heptane was evaporated under reduced pressure to give m-xylyleneglycol dimethyl ether (25.3 g). m-Xylylene glycol dimethyl ether (25.3g) was dissolved in acetic acid (125 ml) and sodium acetate (68 g) wasadded, which was followed by dropwise addition of bromine (68 g) at roomtemperature. The mixture was stirred at room temperature for 3 hr andpoured into 10% aqueous sodium sulfite solution (750 ml), which mixturewas extracted twice with heptane (350 ml). The heptane layer wasextracted twice with 10% aqueous sodium hydroxide solution (150 ml) andonce with water (150 ml). The solvent was evaporated and the residue waspurified by silica gel column chromatography using heptane-ethyl acetate(15:1) as an eluent to give the title compound (10.4 g, yield:29.7%) asa colorless transparent oil.

[0130] 2,4-bis(Methoxymethyl)bromobenzene:

[0131]¹H-NMR(CDCl₃, 400 MHz)δ=3.38(3H,s), 3.53(3H,s), 4.42(2H,s),4.52(2H,s), 7.13(1H,dd,J=8 Hz,J=2 Hz), 7.43(1H,d,J=2 Hz), 7.51(1H,d,J=8Hz) ppm

Example 5

[0132] Synthesis of1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol

[0133] An about 93:7 mixture (34.7 g) of2,4-bis(1′-ethoxyethoxymethyl)bromobenzene and2,6-bis(1′-ethoxyethoxymethyl)bromobenzene was dissolved in dehydratedtetrahydrofuran (250 ml) under a nitrogen atmosphere and cooled to −40°C. Thereto was added dropwise a hexane solution (1.57 mol/L, 64.3 ml) ofn-butyllithium at a temperature of from −40° C. to −30° C. The mixturewas heated to −20° C. and thereto was added dropwisep-fluorobenzaldehyde (12.5 g). The mixture was allowed to warm to 15° C.over 1 hr. The reaction mixture was poured into 20% aqueous ammoniumchloride solution (200 ml) and the organic layer was separated. Theaqueous layer was extracted with toluene (200 ml). The combined organiclayer was washed twice with 20% brine (250 ml) and the solvent wasevaporated. To the residue (38.5 g) was added 60% phosphoric acid (300g) and the resulting solution was stirred at 80-85° C., 9.31-13.3 kPa(70-100 Torr) for 2 hr with heating and cooled to 10° C. The resultingcrystals were collected by filtration, washed thoroughly with ethanoland dried to give1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (20.8 g,88.7%) as fine yellow crystals.

[0134] melting point 101-104° C.;

[0135] IR(KBr)ν=3214(br), 2848(w), 1606(s), 1511(s), 1225(s), 1157(m),1135(m), 1046(s), 1015(s), 824(s), 810(s), 783(m) cm⁻¹;

[0136]¹H-NMR(CDCl₃, 400 MHz)δ=4.72(2H,s), 5.19(1H,d,J=12 Hz),5.31(1H,d,J=12 Hz), 6.14(1H,s), 6.98(1H,d,J=8 Hz), 7.03(2H,t,J=9 Hz),7.24(1H,d,J=8 Hz), 7.29(2H,dd,J=9 Hz,J=6 Hz), 7.32(1H,s) ppm

Example 6

[0137] Synthesis of1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde

[0138] 1-(4′-Fluorophenyl)-1,3--dihydroisobenzofuran-5-ylmethanol (20.6g) was dissolved in ethyl acetate (160 ml) and to the obtained solutionwere added sodium hydrogencarbonate (2.9 g), tetrabutylammonium bromide(1.6 g) and 4-hydroxy-2,2,6,6-tetramethyl-l-piperidinoxy (0.13 g). Themixture was cooled to 5° C. Thereto was added dropwise 12.9% aqueoussodium hypochlorite solution (52.7 g) at 5-10° C. and the mixture wasstirred for 1 hr. Water (100 ml) was added to the reaction mixture andthe mixture was extracted twice with ethyl acetate (100 ml). The extractwas washed with 5% aqueous sodium hydrogencarbonate solution andsaturated brine, and silica gel (3 g) was added. The mixture wasfiltered and the solvent was evaporated to give1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (17.2 g,84.2%).

[0139] n_(D) ²⁴ 1.5823;

[0140] IR(neat)ν=3071(w), 2857(m), 2743(w), 1697(s), 1605(s), 1509(s),1225(s), 1157(m), 1144(m), 1045(s), 832(s), 816(s), 786(m) cm⁻¹;

[0141]¹H-NMR(CDCl₃, 400 MHz)δ=5.25(1H,d,J=13 Hz), 5.38(1H,d,J=13 Hz),6.18(1H,s), 7.06(2H,t,J=9 Hz), 7.16(1H,d,J=8 Hz), 7.30(2H,d,J=9 Hz,J=5Hz), 7.77(1H,d,J=8 Hz), 7.83(1H,s), 10.03(1H,s) ppm

Example 7

[0142] Synthesis of1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde oxime

[0143] 1-(4′-Fluorophenyl)-1,3.-dihydroisobenzofuran-5-carbaldehyde(5.96 g) was dissolved in toluene (30 ml) and triethylamine (2.75 g) wasflown in. Thereto was added hydroxylamine hydrochloride (1.88 g) and themixture was reacted at 80-90° C. for 1 hr. Hot water (30 ml) was addedto the reaction mixture and the mixture was partitioned while hot at 90°C. The organic layer was cooled to 0-5° C. and the resulting crystalswere collected by filtration to give the title compound (5.02 g,yield:79.2%).

[0144] melting point 158-159° C.;

[0145]¹H-NMR(CDCl₃, 400 MHz)δ=5.19(1H,d,J=13 Hz), 5.32(1H,d,J=13 Hz),6.14(1H,s), 7.01(1H,d,J=8 Hz), 7.04(2H,t,J=9 Hz), 7.29(2H,dd,J=9 Hz,J=5Hz), 7.43(1H,d,J=8 Hz), 7.53(1H,s), 7.82(1H,br), 8.16(1H,s) ppm

Example 8

[0146] Synthesis of1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile

[0147] 1-(4′-Fluorophenyl)-1,3--dihydroisobenzofuran-5-carbaldehyde(17.00 g) was dissolved in toluene (200 ml) and hydroxylaminehydrochloride (5.5 g) and triethylamine (8.0 g) were added. The mixturewas stirred at 80-100° C. for 2 hr. The obtained triethylaminehydrochloride was filtered and the solvent was evaporated. Thereto wasadded acetic anhydride (36.5 g) and the mixture was stirred at 125-130°C. for 5 hr. The reaction mixture was poured into 10% aqueous sodiumhydroxide solution (300 ml) and extracted twice with toluene (200 ml).The toluene layer was washed successively with 5% aqueous sodiumhydroxide solution, water and saturated brine and dried over magnesiumsulfate. Silica gel (5 g) was added and the mixture was thoroughlystirred and filtered. The solvent was evaporated to give crude1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (14.2 g).This was recrystallized from a mixed solvent of ethanol/hexane to give1-(4′-fluorophenyl)-1,3-clihydroisobenzofuran-5-carbonitrile (9.52 g,59.8%).

[0148] melting point 96-98° C.;

[0149] IR(KBr)ν=3050(w), 2867(m), 2228(s), 1603(s), 1510(s), 1224(s),1157(m), 1048(s), 1031(s), 832(s) cm⁻¹;

[0150]¹H-NMR(CDCl₃, 400 MHz)δ=5.21(1H,d,J=13 Hz), 5.34(1H,d,J=13 Hz),6.16(1H,s), 7.06(2H,t,J=9 Hz), 7.10(1H,d,J=8 Hz), 7.27(2H,dd,J=9 Hz,J=5Hz), 7.55(1H,d,J=8 Hz), 7.60(1H,s) ppm

Reference Example 1

[0151] Synthesis of m-xylylene glycol diacetate

[0152] m-Xylylene dichloride (25.0 g, 143 mmol) and potassium acetate(34.0 g, 171 mmol) were suspended in acetone (125 ml). To the suspensionwas added benzyltriethylammonium chloride (4.8 g) and the mixture wasrefluxed for 2.5 hr. The reaction mixture was cooled and filtered. Thesolvent was evaporated and toluene (50 ml) was added. The toluene layerwas washed with water (50 ml) and saturated brine (50 ml) and thesolvent was evaporated to give m-xylylene glycol diacetate (31.3 g,98.7%) as an oil.

Reference Example 2

[0153] Synthesis of1-(3′-dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile(citalopram)

[0154] 60% Sodium hydride (0.92 g) was dispersed in THF (30 ml). To theobtained suspension was added dropwise a solution of1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (4.80 g) inTHF (10 ml) at 40-50° C. The mixture was stirred at the same temperaturefor 30 min, and a solution of 3-dimethylaminopropyl chloride (3.2 g) intoluene (20 ml) was added dropwise, which was followed by stirring for10 min. Then, dimethyl sulfoxide (30 ml) was further added dropwise andthe mixture was stirred at 65-70° C. for 3 hr. The reaction mixture waspoured into ice water (200 ml) and extracted 3 times with toluene (60ml). The organic layer was extracted twice with 20% aqueous acetic acid(60 ml). The aqueous layer was neutralized, extracted twice with toluene(60 ml) and washed with water. Anhydrous potassium carbonate (2 g) andsilica gel (2 g) were added and the mixture was stirred and filtered.The solvent was evaporated to give1-(3′-dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile(citalopram base) as a viscous oil (3.37 g, 51.6%).

[0155] This oil was converted to hydrobromide by a conventional method.The melting point of the obtained crystals was 184-186° C.

[0156]¹H-NMR(CDCl₃, 400 MHz)δ=1.26-1.52(2H,m), 2.11-2.26(4H,m),2.13(6H,s), 5.15(1H,d,J=13 Hz), 5.19(1H,d,J=13 Hz), 7.00(2H,t,J=9 Hz),7.41(1H,d,J=8 Hz), 7.43(2H,dd,J=9 Hz,J=5 Hz), 7.50(1H,s), 7.59(1H,d,J=8Hz) ppm

[0157] According to the present invention, an industrially advantageousproduction method capable of producing a 5-phthalancarbonitrile compoundat a high yield can be provided without using a reagent that imposes agreat burden on the environment (with small environmental burden), suchas heavy metal, metal cyanide and thionyl chloride. From the obtained5-phthalancarbonitrile compound, citalopram useful as an antidepressantcan be provided.

[0158] This application is based on a patent application No. 311703/1999filed in Japan, the contents of which are hereby incorporated byreference.

What is claimed is:
 1. A compound of the formula [I]

wherein X is chlorine atom, bromine atom or iodine atom.
 2. A compoundof the formula [II]

wherein R¹ is alkanoyl having 2 to 5 carbon atoms, alkyl having 1 to 5carbon atoms, tetrahydropyran-2-yl, alkoxymethyl wherein an alkoxylmoiety has 1 to 5 carbon atoms, 1-alkoxyethyl wherein an alkoxyl moietyhas 1 or 3 to 10 carbon atoms, or trialkylsilyl wherein each alkylmoiety has 1 to 5 carbon atoms, and X is chlorine atom, bromine atom oriodine atom.
 3. The compound of claim 2 wherein R¹ is acetyl and X isbromine atom.
 4. A compound of the formula [III]


5. A compound of the formula [IV]


6. An oxime compound of the formula [V]


7. A production method of a compound of the formula [I]

wherein X is chlorine atom, bromine atom or iodine atom, which comprisessubjecting a compound of the formula [A]

wherein R² is alkanoyl having 2 to 5 carbon atoms, to chlorination,bromination or iodination and then to elimination of the alkanoyl group.8. A production method of a compound of the formula [III]

which comprises the steps of (1) converting a compound of the formula[II-b]

wherein R^(1b) is alkyl having 1 to 5 carbon atoms,tetrahydropyran-2-yl, alkoxymethyl wherein an alkoxyl moiety has 1 to 5carbon atoms, 1-alkoxyethyl wherein an alkoxyl moiety has 1 to 10 carbonatoms, or trialkylsilyl wherein each alkyl moiety has 1 to 5 carbonatoms, and X is chlorine atom, bromine atom or iodine atom, to aGrignard reagent or lithium compound, (2) coupling same withp-fluorobenzaldehyde, and (3) subjecting the obtained coupling compoundto deprotection of R^(1b) and cyclization.
 9. A production method of theformula [IV]

which comprises oxidizing a compound of the formula [III]


10. A production method of an oxime compound of the formula [V]

which comprises reacting a compound of the formula [IV]

with hydroxylamine or a mineral acid salt thereof.
 11. A productionmethod of a 5-phthalancarbonitrile compound of the formula [VI]

which comprises dehydrating an oxime compound of the formula [V]


12. A production method of 5-phthalancarbonitrile compound of theformula [VI]

which comprises reacting a compound of the formula [IV]

with hydroxylamine or a mineral acid salt thereof and dehydrating theresulting compound.
 13. A production method of a compound of the formula[II′]

wherein R^(1′)is alkanoyl having 2 to 5 carbon atoms, alkyl having 1 to5 carbon atoms, tetrahydropyran-2-yl, alkoxymethyl wherein an alkoxylmoiety has 1 to 5 carbon atoms, 1-alkoxyethyl wherein an alkoxyl moietyhas 1 to 10 carbon atoms, or trialkylsilyl wherein each alkyl moiety has1 to 5 carbon atoms, and X is chlorine atom, bromine atom or iodineatom, which comprises (1) converting the hydroxyl group of a compound ofthe formula [I]

wherein X is chlorine atom, bromine atom or iodine atom, to alkoxyhaving 1 to 5 carbon atoms, tetrahydropyran-2-yloxy, alkoxymethoxywherein an alkoxyl moiety has 1 to 5 carbon atoms, 1-alkoxyeth oxywherein an alkoxyl moiety has 1 to 10 carbon atoms, or trialkylsilyloxywherein each alkyl moiety has 1 to 5 carbon atoms, or (2) subjecting acompound of the formula [A]

wherein R² is alkanoyl having 2 to 5 carbon atoms, to chlorination,bromination or iodination.